Parkinson's disease (PD) poses a serious threat to the health of a large segment of our society. This is an extensively revised renewal application for a Program Project Grant now in its 18th year. During much of the history of the PPG, we have focused on the compensatory changes that underlie the preclinical phase of PD. That line of investigation will continue, while at the same time we will also add two new foci: first, the development of neuroprotective strategies and, second, the detection of PD it its preclinical phase. Neuroprotection: This will now provide the principal long-term focus of the entire PPG. Our approach derives from recent evidence from our labs indicating that the contralateral motor neglect and loss of DA normally following unilateral damage to the nigrostriatal DA projection can be ameliorated by forced use of the contralateral limb. We hypothesize that forced execution of a motor act that is otherwise compromised by PD is neuroprotective, and that this results from an interaction between the motor act, injury, and concomitant increase in the availability of one or more trophic. We will explore this hypothesis using our 6-hydroxydopamine (6-OHDA) rat model. Our work will involve studies of the role of trophic factors (e.g., GDNF, BDNF, and FGF2), estrogen, and aging, as well as anatomical studies to differentiate between protection, rescue and sprouting (Project 1: M. Zigmond, PI). We also use multineuron recording in awake animals to examine the effect of forced use on the functioning of the basal ganglia more broadly (Project 2, D. Woodward, PI). Compensation: In the past, our studies of compensation have focused our studies on adaptations within the nigrostriatal dopamine (DA) system. Our multineuron recordings will now allow us to explore adjustments within other components of the basal ganglia (Project 2: D. Woodward, PI). Early detection: For neuroprotective strategies to be most effective, it is likely that they must be applied as early in the course of the disease as possible. In this respect, the compensatory changes noted above represent a problem to be overcome through the development of diagnostic tests that can detect PD before the emergence of gross neurological deficits. To do so we will develop a multi-dimensional clinical test battery, using PET imaging as the ultimate criteria for nigrostriatal damage (Project 3, N. Bohnen, PI). We believe that by combining a variety of basic, translational, and clinical approaches we will make significant progress toward the development of a therapeutic approach to PD.